Maintaining Skeletal Muscle Mass: Lessons Learned From Hibernation ABSTRACT (Area of Science: Clinical and Translational Research) Skeletal muscle is the largest organ in the human body comprising ~50% of the body's weight. Maintenance of normal muscle mass and physiology is essential for health. Disuse (e.g.,immobilization, denervation, and microgravity) and aging result in debilitating loss of skeletal muscle. An estimated $26 billion dollars of annual healthcare costs are attributed to complications directly associatedwith age-related loss of muscle mass alone. This does not account for the cost of the plethora of clinical diseases including cancer, sepsis, diabetes, AIDS, and neurodegenerative disorders which are associated with varying degrees of muscle atrophy and dysfunction. Satellite cells are primary stem cells in adult skeletal muscle and are responsible for the postnatal maintenance, growth, repair, and regeneration of skeletal muscles. Loss of muscle mass is the net result of a decrease in satellite cell number and/or impaired proliferation, associated with increased muscle proteolysis and decreased protein synthesis. In stark contrast to the above, hibernating mammals have evolved mechanisms to survive prolonged immobility without pathologic loss/atrophy of muscle mass. The molecular mechanisms underlying this fascinating phenomenon are largely unknown. This innovative and novel project will for the first time apply knowledge of normal mechanisms of muscle protection in the hibernating mammal to the disease process of disuse muscleatrophy in non- hibernating mammals. This will provide unique insights into the fundamental cellular and molecular pathways underlying skeletal muscle atrophy and the protection against it. The proposed in-depth investigation of satellite cells provides the first analysis of a stem cell in any hibernating animal. Furthermore, applying the novel gene expression-based high-throughput screening approach will enable the identification of drugs which may provide novel therapeutic interventions for a broad group of patients with skeletal muscle atrophy and degeneration.